Rapid MALDI-MS Assays for Drug Quantification in Biological Matrices: Lessons Learned, New Developments, and Future Perspectives.

Margaux Fresnais,Esra Yildirim,Walter E Haefeli,Rémi Longuespée,Dirk Jäger,Stefan M Pfister,Seda Karabulut,Jürgen Burhenne,Julia Benzel,Kristian W Pajtler,Inka Zörnig

doi:10.3390/molecules26051281

Abstract

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has rarely been used in the field of therapeutic drug monitoring, partly because of the complexity of the ionization processes between the compounds to be quantified and the many MALDI matrices available. The development of a viable MALDI-MS method that meets regulatory guidelines for bioanalytical method validation requires prior knowledge of the suitability of (i) the MALDI matrix with the analyte class and properties for ionization, (ii) the crystallization properties of the MALDI matrix with automation features, and (iii) the MS instrumentation used to achieve sensitive and specific measurements in order to determine low pharmacological drug concentrations in biological matrices. In the present hybrid article/white paper, we review the developments required for the establishment of MALDI-MS assays for the quantification of drugs in tissues and plasma, illustrated with concrete results for the different steps. We summarize the necessary parameters that need to be controlled for the successful development of fully validated MALDI-MS methods according to regulatory authorities, as well as currently unsolved problems and promising ways to address them. Finally, we propose an expert opinion on future perspectives and needs in order to establish MALDI-MS as a universal method for therapeutic drug monitoring.

Highlights

Using recent developments performed with an Matrix-assisted laser desorption/ionization (MALDI)-ion mobility-tandem mass spectrometry (IM-MS/MS) assay for the quantification of the model drug MBZ in tissue sections applying a profiling method [11] can help illustrate current methodological challenges and new developments for addressing them
Using the MALDI matrix 2,5-DHB, which is known to be versatile for the ionization of small compounds, including the model drug MBZ, we could evaluate the usefulness of ion mobility spectrometry (IMS) as a post-ionization separation method to increase the selectivity of analyses after data extraction [11]
Developments started with a standard MALDI-MS assay to quantify the intact compound in the tissue sections, and the MS method was gradually modified by adding IM separation and MS/MS fragmentation to reach a multiple reaction monitoring (MRM)-like method based on the monitoring of a fragment ion with an m/z specific to the compound of interest

Summary

Introduction

Liquid chromatography coupled to electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) has become the gold standard for the quantification of most drugs in diverse biological matrices. LC allows for the separation of drugs from endogenous compounds co-extracted from the biological matrix. ESI is a widely described ion source for drug quantification, which relies on well-described electrochemical processes [1]. For this reason, LC-ESI-MS/MS does not require an extensive knowledge of complex ionization processes before routine use for diverse applications. Methods for MS analyses of surfaces are progressively emerging as options for drug quantification from biological matrices [2,3]

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